Factores de riesgo para carcinoma de endometrio de alto grado / Risk factors for high-grade endometrial carcinoma

El carcinoma de endometrio (CE) ha sido dividido de forma clásica en 2grupos: el tipo I, considerado de buen pronóstico y estrógeno dependiente y el tipo II, de peor pronóstico y estrógeno independiente. Esta subdivisión etiopatogénica no está tan clara cuando se habla de CE de alto grado. El objetivo del estudio es analizar los factores de riesgo asociados al CE de alto grado. Material y métodos: Estudio retrospectivo de cohortes multicéntrico en 3hospitales españoles de tercer nivel, Hospital Universitario Miguel Servet en Zaragoza, Hospital Clínico San Carlos en Madrid y Hospital Virgen del Rocío en Sevilla, en el que se estudió la presencia de los factores de riesgo asociados al CE de alto grado histológico: endometrioide G3 (CEG3), carcinoma seroso (CS), carcinoma de células claras (CCC) y carcinosarcoma uterino o tumor mülleriano mixto maligno (TMMM). Se analizaron las posibles diferencias entre los subtipos y atendiendo a si se trataba de CE tipo I/II. Se incluyeron 373 CE de alto grado, de ellos, 135 fueron CEG3 o de tipo I y 238 de tipo II: 96 CS, 64 CCC y 78 TMMM. Resultados: La diabetes, obesidad, nuliparidad y utilización de tratamiento hormonal de reemplazo no mostraron diferencias significativas entre los subtipos. El TMMM fue el que con menor frecuencia se asoció a HTA y, por el contrario, el que mostró mayor asociación a la utilización de tamoxifeno. Conclusiones: Los factores de riesgo asociados a CE de alto grado son similares en el tipo I y II

Endometrial carcinoma (EC) has traditionally been divided into 2groups: type I, considered to have a good prognosis and to be oestrogen-dependent and type II, with a poorer prognosis and oestrogen-independent. The aim of the study is to analyse the risk factors associated with high-grade EC. Material and Methods: Retrospective multicentre cohort study in 3Spanish reference hospitals: Hospital Universitario Miguel Servet in Zaragoza, Hospital Clínico San Carlos in Madrid and Hospital Virgen del Rocío in Seville. We studied the presence of risk factors associated with high grade EC: G3 endometrioid (G3EC), serous carcinoma (SC), clear cell carcinoma (CCC) and malignant mixed mesodermal tumours (MMMT). Differences between subtypes were analysed depending on whether the EC was type I or II. A total of 373 cases of high-grade EC were included, of which 135 were G3EC or type I and 238 were type II (96 SC, 64 CCC and 78 MMMT). Results: Diabetes, obesity, nulliparity and use of hormonal replacement therapy showed no significant difference between subtypes. MMMT was less frequently associated with hypertension and conversely it showed greater association with the use of tamoxifen. Conclusions: Risk factors associated with high-grade EC are similar in type I and II

Primary ovarian malignant mixed mesodermal tumor: report of four cases.

Malignant mixed mesodermal tumors (MMMTs) are highly aggressive and usually diagnosed at advanced stages. MMMT originates from either the ovary or the uterus. Because this disease is relatively rare, an optimal treatment modality has not yet been established. The authors report four cases of ovarian MMMT (one heterologous MMMT and three homologous MMMTs) during 1990-2011. The patients underwent operation immediately after histopathologically confirmation and were treated with platinum-based combination chemotherapy. The extent of operation, the outcomes of radiation therapy, and the proper chemotherapeutic regimen are still controversial. The authors report herein four cases of ovarian MMMTs alone with a brief literature review.

Endometriosis and ovarian cancer: clinical and molecular aspects.

Endometriosis is one of the most commonly encountered benign problems in gynecology. Even though endometriosis appears to predispose to ovarian cancer the progression from atypical epithelial proliferation (atypical endometriosis and metaplasia), to the formation of well-defined borderline tumors and finally to endometrioid ovarian cancer will take several years. To elaborate on the concept of endometriosis as a precursor of some types of ovarian cancer, we present an overview of the pathophysiological and genetic characteristics, common in those two conditions. Furthermore, we present the genetic mutations found in ovarian cancers and we outline the common genetic alterations of endometriosis and ovarian cancer, focusing on the PI3K/Akt/mTOR-signaling pathway.

A comprehensive review of the retroperitoneal anatomy, neoplasms, and pattern of disease spread.

A clear understanding of the normal anatomy and pattern of disease spread is important in evaluating many retroperitoneal disorders. Primary retroperitoneal tumors are uncommon, accounting for 0.1%-0.2% of all malignancies in the body; 80%-90% of all primary retroperitoneal tumors are malignant. The primary retroperitoneal neoplasms can be divided into solid or cystic masses. The solid neoplasms can be classified according to their tissue of origin into 3 main categories: mesodermal tumors, neurogenic tumors, and extragonadal germ cell tumors. Computed tomography and magnetic resonance imaging play a vital role in the localization, characterization, evaluation of the extent of local invasion, assessment of metastases, and determination of treatment response for these tumors. The diagnosis of a primary retroperitoneal malignancy is often challenging owing to overlap of imaging findings. A definitive diagnosis can be established only at histopathologic analysis. However, knowledge of the important tumor characteristics, growth pattern, and vascularity can assist in narrowing the differential diagnosis.

Activity of pegylated liposomal doxorubicin for extragenital mullerian adenosarcoma with sarcomatous overgrowth: a case report and a review of the literature.

A 47-year-old woman was diagnosed with extragenital mullerian adenosarcoma with sarcomatous overgrowth. One month after her initial surgery, the patient developed pelvic recurrence, which was completely excised by surgery. However, one month later, the patient developed further recurrences in her pelvis and upper abdomen. A clinical complete response was achieved with three cycles of liposomal doxorubicin and is currently clinically free of disease. So far, including the present case, 23 cases of extragenital mulleian adenosarcoma have been reported in the English literature. Because of the rarity of the reported cases, there are no treatment guidelines based on a good level of evidence. In the current report, through a literature review, we provide information on the activity of pegylated liposomal doxorubicin for extragenital mullerian adenosarcoma with sarcomatous overgrowth.

[Sarcomas and mixed mesodermal tumors of the uterus]. / Mesenchymale Tumoren des Uterus.

Malignant mesodermal tumors of the uterus are an inhomogenous group of uterine malignancies with different pathogenesis, clinical presentation and prognosis. These rare tumors represent approximately 1 % of all uterine malignancies. The aggressive carcinosarcomas or mixed muellerian tumors are defined by mixed malignant epithelial and malignant mesodermal histopathology and are of the same precursor cell origin like endometrial cancer. Thus, carcinosarcomas were reclassified by the FIGO as an aggressive type of endometrial cancer and treated like type II endometrial cancer. Adenosarcomas are also mixed tumors with benign epithelial proliferation and malignant mesodermal cell growth, have a good prognosis and represent less than 5 % of all mesodermal uterine malignancies. Besides carcinosarcomas, the pure mesodermal leiomyosarcomas are the most common mesodermal malignancies. Patients with leiomyosarcamos are usually perimenopausal, and although more than half of the patients present with symptoms, diagnosis occurs incidentally in most cases in final histopathologic workup of an excised putative myoma or uterus. Adequate anamnesis, gynecologic examination and careful imaging by transvaginal ultrasound in the preoperative setting might hint to correct differential diagnosis in many cases. Overall the prognosis of uterine leiomyomas is poor. Malignancies of the endometrial stroma are very rare and divided in two subgroups, the mostly estrogen receptor positive endometrial stromal sarcoma, which occur preferably in premenopausal women and show a favorable prognosis, and the very aggressive undifferentiated endometrial sarcomas. The more rare undifferentiated endometrial sarcomas occur in postmenopausal women and most patients die in the first two years after diagnosis. Risk stratification of preoperative differential diagnosis requires improvements and the correct histopathologic workup of mesodermal uterine malignancies is still a challenge for pathologists.

[Primary ovarian malignant mixed mesodermal tumor (MMMT) as a second primary tumor in a patient with invasive breast carcinoma--case report]. / Maligni mijesani mezodermalni tumor jajnika (MMMT)--drugi primarni tumor u bolesnice s invazivnim karcinomom dojke.

Malignant mixed mesodermal tumor (MMMT) of the ovary is a rare aggressive tumor that consists of an epithelial (carcinoma) and a stromal (sarcoma) component. MMMT accounts for less than 2% of ovarian cancers and has a very poor prognosis. We present a case and difficulties of diagnosing an ovarian MMMT in a postmenopausal woman with a history of invasive breast carcinoma treated postoperatively with radiotherapy and tamoxifen. A 52-year-old patient presented with unilateral ovarian tumor and moderately elevated CA125 (107 U/mL) and underwent laparotomy. Fine needle aspiration of the ovary and ascites for cytologic analysis, and tumor biopsy for histopathology were performed intraoperatively. Intraoperative cytologic sample showed necrotic background with rare single malignant cells with pale, abundant cytoplasm and conspicuous nucleoli suggesting clear cell carcinoma. Ascites sample showed inflammatory and reactive background with suspected papillary formations mimicking adenocarcinoma. Postoperatively, cytochemical PAS staining and immunocytologic staining with epithelial antigen (EA), cytokeratin (CK)7 and vimentin showed EA and PAS positivity for ovarian tumor, and EA and CK7 for ascites, suggesting a clear cell carcinoma. Histology revealed ovarian clear cell carcinoma. Three months later, the patient underwent hemicolectomy because of tumors on the right large bowel serosa with intraoperative morphological finding of metastatic malignant tumor without other specific features. Postoperative morphological analysis and immunohistochemical staining of the tumor revealed two malignant components, epithelial and stromal one. Repeat histologic analysis of the ovarian tumor confirmed ovarian MMMT (with a clear cell carcinoma component). Other studies of breast cancer emphasize that patients with invasive breast cancer and mutations of BRCA1 and BRCA2 genes are at an increased risk of primary ovarian cancer. Our study confirmed it and suggested considering a second primary malignant tumor of ovarian origin in patients with a history of breast carcinoma, postoperatively treated with radiotherapy and tamoxifen. Although rare, second primary ovarian tumors may present as MMMT.

Ovarian malignant mixed mesodermal tumor with neuroectodermal differentiation: a multifaceted evaluation.

Malignant mixed mesodermal tumors (MMMTs) of the ovary are rare, highly aggressive neoplasms that arise most commonly in postmenopausal women. Histologically, they consist of a mixed population of malignant epithelial and mesenchymal elements. Neuroectodermal differentiation in ovarian MMMTs is exceedingly uncommon, with only a few case reports in the literature. We present a case of an ovarian MMMT with neuroectodermal differentiation in a 78-year-old female patient. Histologically, the tumor was composed of epithelial, mesenchymal, and neuroectodermal elements. The neuroectodermal component was predominantly that of a medulloepithelioma, with scattered areas displaying features of an anaplastic astrocytoma, including rare ganglion cell differentiation. The neuroectodermal component showed immunoreactivity for glial fibrillary acidic protein, synaptophysin, and S100 protein. Ultrastructurally, the neuroectodermal component was populated by cells with irregular nuclei, finely dispersed chromatin, rudimentary cell junctions, and a delicate basement membrane, all of which have been described in medulloepitheliomas. DNA ploidy analysis was also performed on the various components of the tumor and compared with 3 additional cases of MMMT without neuroectodermal differentiation and 2 ovarian immature teratomas. Our findings suggest that the neuroectodermal component may arise from a separate clone or at least evolves at an earlier stage of tumor development.

A pilot study of cisplatin, ifosfamide and mesna in the treatment of malignant mixed mesodermal tumors of the ovary.

PURPOSE: To evaluate the efficacy and toxicity of cisplatin and ifosfamide in the treatment of patients with malignant mixed mesodermal tumor (MMMT) of the ovary. METHODS: Ten patients with histologically confirmed primary MMMT of the ovary diagnosed between 1993 and 2001 were enrolled in the study. Treatment consisted of cisplatin 75 mg/m2 on day 1, followed by ifosfamide 2.0 g/m2 over 24 h on days 1, 2 and 3. Mesna, 400 mg/m2, was given IV immediately prior to and 4 and 8 h after the start of each ifosfamide infusion. Chemotherapy was repeated on a 28-day cycle if blood counts permitted. Standard response criteria were used. Nine patients were evaluable for response. RESULTS: Eight of the nine patients responded to therapy, with 7 complete responses (78%) and 1 partial response. Seven of the eight responders (87.5%) eventually recurred. The median progression-free survival was 10 months (range 0-94.4 months). The median overall survival was 17.1 months (range 8-125.5 months). One patient remained free of disease 94.4 months after diagnosis, and one patient remained alive with recurrence 125.5 months following diagnosis. There were 13 grade 3 toxicities and 4 grade 4 toxicities. Four patients had grade 4 and three had grade 3 neutropenia, all of which required dose reductions. CONCLUSION: The combination of cisplatin and ifosfamide/mesna demonstrated activity against MMMT of the ovary. Response durations were short, however, and the regimen was associated with significant toxicity. Novel agents with activity against MMMT of the ovary and acceptable toxicity are needed.

Primary malignant mesodermal ovarian sarcomas.

Primary malignant mesodermal ovarian sarcomas are rare tumors and have a poor prognosis. The disease is usually diagnosed at a late stage and 5-year survivals are uncommon. Most patients are treated with debulking surgery followed by adjuvant chemotherapy. We report ten patients treated at a single institution. All patients underwent surgery and 90% received adjuvant chemotherapy. The median survival was 20 months, and only one patient survived beyond 5 years. Newer treatment strategies are urgently needed in the management of this disease.

Mesodermal adenosarcoma of the testis.

Biphasic neoplasms with a benign to atypical epithelial component and a usually low-grade malignant stromal component have been reported in various sites, probably being best known for their occurrence in the uterine corpus (mullerian adenosarcoma). We report a tumor of this type that occurred in the testis of a 76-year-old man and, to our knowledge, is the first mesodermal adenosarcoma reported at this site. The patient had scrotal swelling for many years with a pronounced increase in the swelling over the past 2 years. A large complex solid-cystic testicular tumor was evident on ultrasound, and examination of a radical orchiectomy specimen showed a 6.5-cm mass. On microscopic examination, the neoplasm had a phyllodes-like appearance with bland cuboidal to flattened epithelium covering polypoid fronds, and lining glands and cysts. The stroma varied from cellular, particularly where it condensed around the glands and cysts, to hypocellular and hyalinized. It was immunoreactive for muscle specific actin, CD10, and to a lesser degree, desmin. This case expands the known sites where mesodermal adenosarcoma may occur. The histogenesis is speculative, but possible options are discussed.

Adjuvant ifosfamide and cisplatin in patients with completely resected stage I or II carcinosarcomas (mixed mesodermal tumors) of the uterus: a Gynecologic Oncology Group study.

OBJECTIVES: To determine progression-free survival (PFS) and overall survival (OS) in women with completely resected stage I or II carcinosarcoma of the uterus treated with adjuvant ifosfamide and cisplatin, and to assess the toxicity of this regimen. METHODS: Eligible patients had histologically confirmed carcinosarcoma (mixed mesodermal tumor) and no postoperative radiotherapy following complete resection for clinical stage I or II disease. They were to have adequate renal, hepatic, and hematologic functions and performance status of 2 or less. Study entry was to be within 8 weeks of hysterectomy. Patients with previous chemotherapy, or other noncutaneous malignancies, were ineligible. Ifosfamide was administered 1.5 g/m2 intravenously (IV) over 1 h and cisplatin was given 20 mg/m(2) over 15 min followed by mesna 120 mg/m2 IV bolus, then 1.5 g/m2/24 h as a continuous infusion. Initial doses (daily x 5 every 21 days x 3 cycles) were reduced by 20% (to 4 days) for myelotoxicity. RESULTS: Nine of seventy-six patients enrolled were deemed ineligible and another two who did not receive protocol treatment were inevaluable. Of the 65 evaluable patients, median age was 65 years; 50 patients (77%) were stage I and 15 (23%) were stage II. PFS and OS, respectively, were 69% and 82% at 24 months, and 54% and 52% at 84 months. Overall 5-year survival was 62%. Leukopenia was the most commonly reported, but manageable, toxicity. CONCLUSION: Adjuvant ifosfamide and cisplatin after primary surgery for stage I or II carcinosarcoma of the uterus is tolerable. In the absence of concurrent controls, the impact on PFS and OS is unclear. Pelvic relapse remains problematic.

Simultaneous bilateral occurrence of a mixed mesodermal tumor and cystadenocarcinoma in the ovary.

The mixed mesodermal tumor is a very uncommon malignancy. The aggressiveness of this lesion is illustrated by extremely poor prospects for afflicted patients: postoperative survival is usually shorter than 24 months. According to the literature, malignant mixed tumor of the ovary is rather rare and its occurrence with other malignancy is exceptional. We report here a case of a 62-years old woman with serous cystadenocarcinoma in the right ovary and a heterologous malignant mixed mesodermal tumor in the left one. Both tumors expressed cytokeratins, while only the mesodermal tumor expressed S-100 and focal NSE.

[Malignant mixed mesodermal tumor: histo- and cytopathologic correlations]. / Tumora mixta mezodermica maligna. Corelatii cito-histopatologice.

To correlate the cytopathological and the histopathological findings in uterine mixed mesodermal malignant tumor (MMMT) we have examined the cervical smear, endometrial curettage and hysterectomy specimen of a patient diagnosed with uterine tumor. The smear was stained by Papanicolaou staining and the tissue processed by routine technique and stained H&E. The original cytological diagnosis was adenosquamous carcinoma. The histopathological diagnosis was MMMT of heterologous type. A review of the smear revealed features which may orientate the diagnosis: multinucleate cells, isolated cells with cyanophilic cytoplasm, hyperchromatic nuclei and prominent nucleoli, elongated cyanophilic cells of sarcomatous origin. We conclude that the cytopathological diagnosis of the MMMT in cervical smears is very difficult. This may be sustained by the evidence of more cell types and cellular features orientating to a sarcomatous origin. The most important differential diagnosis is adenosquamous carcinoma.

Malignant mixed mesodermal tumor in a young woman with polycystic ovary syndrome. A case report.

BACKGROUND: Malignant mixed mesodermal tumors (MMMTs) are uncommon, highly aggressive tumors of the uterus composed of both carcinomatous and sarcomatous elements, both likely to be derived from the same original stem cell. There is a strong association between endometrial adenocarcinoma and polycystic ovary disease. However, only two cases of MMMT occurring in women with polycystic ovaries have been reported. CASE: A 36-year-old woman with polycystic ovary disease developed an MMMT of the endometrium. CONCLUSION: Some cases of MMMT may be estrogen related.

Malignant mixed mesodermal tumours: biology and clinical aspects.

Mixed mesodermal tumours (MMTs) are relatively rare gynaecological tumours that have been poorly studied in clinical and molecular terms. They are chemosensitive (at least initially), although ultimately they have a poor prognosis. The biology of the tumour is fascinating in view of its composition of both epithelial and mesenchymal entities. We review herein the literature on the clinical and biological aspects of this malignancy.

Incidental finding of malignant mixed mesodermal tumor at hysterectomy for uterine prolapse. A case report.

BACKGROUND: The finding of unanticipated pathology in a uterus after vaginal hysterectomy for prolapse is uncommon. CASE: An incidental small malignant mixed mesodermal tumor was found at vaginal hysterectomy in a 68-year-old woman. CONCLUSION: A MED-LINE search found no other reported cases of malignant mixed mesodermal tumor in a patient undergoing vaginal hysterectomy for uterine prolapse. Unexpected endometrial and cervical lesions will be discovered occasionally after hysterectomy for benign disease.

Coexistent choriocarcinoma and malignant mixed mesodermal tumor of the uterus.

OBJECTIVE: The purpose of this article is to report a case of coexisting uterine choriocarcinoma and uterine malignant mixed mesodermal tumor (MMMT). The relevant literature is reviewed and possible pathogenesis discussed. METHODS: The clinical course and histopathology of the case were reviewed and a Medline literature search for other cases was performed. RESULTS: The patient's uterine tumor contained syncytiotrophoblastic and cytotrophoblastic cells that stained positively for the beta subunit of human chorionic gonadotrophin consistent with uterine choriocarcinoma. Pathology also revealed a second distinct neoplasm composed of adenocarcinoma admixed with sarcoma, compatible with a uterine MMMT. The patient experienced metastatic choriocarcinoma to her lungs, lymph nodes, and brain. She suffered a complicated clinical course and died 7 months after her initial diagnosis. The literature search revealed that various gynecologic and nongynecologic carcinomas with trophoblastic differentiation have been described, but an association with uterine MMMT has not been previously reported. CONCLUSIONS: Trophoblastic differentiation and choriocarcinoma associated with gynecologic and nongynecologic tumors is rare. We document the presence of uterine MMMT coexisting with uterine choriocarcinoma that followed an aggressive clinical course and review the possible pathogenesis of this lesion.

Pelvic malignant mixed mesodermal tumor of uncertain origin: a case report.

Extra-uterine, and especially extragenital, malignant mixed mesodermal tumors (MMMT) are very rare. A large intrapelvic tumor resected from a 56-year-old woman was investigated with morphological and immunohistochemical methods. A large, soft and fragile tumor was located in the pelvic space. The tumor showed high cellularity and was biphasic; it consisted of an admixture of adenocarcinoma and various kinds of sarcomas. The latter were comprised of high-grade endometrial stromal sarcoma, pleomorphic sarcoma, and chondrosarcoma. The pleomorphic sarcoma showed a storiform pattern. The periodic acid-Schiff-positive eosinophilic hyaline droplets and globules in multinucleated giant cells revealed a typical ring-like or peripheral staining for alpha-1-antitrypsin and alpha-1 antichymotrypsin. We considered this case to be pelvic MMMT of uncertain origin, heterologous type.